Abstract
Puberty is a critical period in mesocorticolimbic dopamine (DA) system development, particularly for the medial prefrontal cortex (mPFC) projection which achieves maturity in early adulthood. The guidance cue netrin-1 organizes neuronal networks by attracting or repelling cellular processes through DCC (deleted in colorectal cancer) and UNC-5 homologue (UNC5H) receptors, respectively. We have shown that variations in netrin-1 receptor levels lead to selective reorganization of mPFC DA circuitry, and changes in DA-related behaviors, in transgenic mice and in rats. Significantly, these effects are only observed after puberty, suggesting that netrin-1 mediated effects on DA systems vary across development. Here we report on the normal expression of DCC and UNC5H in the ventral tegmental area (VTA) by DA neurons from embryonic life to adulthood, in both mice and rats. We show a dramatic and enduring pubertal change in the ratio of DCC:UNC5H receptors, reflecting a shift toward predominant UNC5H function. This shift in DCC:UNC5H ratio coincides with the pubertal emergence of UNC5H expression by VTA DA neurons. Although the distribution of DCC and UNC5H by VTA DA neurons changes during puberty, the pattern of netrin-1 immunoreactivity in these cells does not. Together, our findings suggest that DCC:UNC5H ratios in DA neurons at critical periods may have important consequences for the organization and function of mesocorticolimbic DA systems.
Highlights
The elaboration and establishment of organized patterns of neural connectivity during brain development rely on the concerted action of various permissive and instructive cues
The dcc +/2 dopamine and behavioral phenotypes are not evident before puberty [20], demonstrating a critical temporal window of vulnerability within the mesocorticolimbic DA system to the effects of reduced DCC levels. These findings indicate that netrin-1 receptors participate in the development of the mesocorticolimbic DA system and that their organizational effects occur at specific critical periods
The major finding of this study is that the expression pattern of the netrin-1 receptors DCC and UNC-5 homologue families (UNC5H) by ventral tegmental area (VTA) DA neurons shifts dramatically at the peri-pubertal period in both rats and mice
Summary
The elaboration and establishment of organized patterns of neural connectivity during brain development rely on the concerted action of various permissive and instructive cues. Netrin-1, a member of the netrin family of guidance cues, participates in the organization of neural networks by attracting or repelling extending processes [1] [2] [3]. Whereas DCC receptors mediate attraction, DCC-UNC5H receptor complexes, or UNC5H alone, mediate repulsion [1] [2] [4] [5][6]. Consistent with their function, these netrin-1 receptors recruit downstream proteins that regulate cytoskeletal reorganization [7]. Netrin-1 mediated signal transduction via DSCAM is poorly understood
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